15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Coronary-Artery-Disease

Internal mammary artery (IMA) and radial artery (RA) are the 2 main arterial conduits used in coronary artery bypass grafting (CABG). The aim of this study was to analyze in vitro the vasoreactive properties in both vessels and to investigate the effects of pravastatin incubation on vascular function. IMA and RA rings obtained from patients undergoing CABG were studied in organ baths. We examined the contractile responses to phenylephrine and U46619 and the relaxation to acetylcholine (ACh) and sodium nitroprusside. In another series of experiments, the vascular reactivity and the superoxide anion production were studied after incubation with pravastatin. The effect of mevalonic acid on such responses was also assessed. Our results show that RA significantly evoked greater tension in response to vasoconstrictor agents and higher relaxation to ACh than IMA. In contrast, relaxation induced by sodium nitroprusside was not significantly different. Incubation with pravastatin reduced the contractile response to U46619 and improved the endothelium-dependent relaxation to ACh in both arteries. Whereas the effect of pravastatin on response to U46619 was completely abolished by coincubation with mevalonic acid, only a partial inhibition on ACh relaxation was observed. In conclusion, in vitro incubation with pravastatin enhanced endothelial function in IMA and RA. This suggests that postoperative (may include intraoperative) administration of statins could improve the endothelial function of arterial grafts in patients undergoing CABG.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Aged; Coronary Artery Bypass; Coronary Artery Disease; Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mammary Arteries; Nitroprusside; Phenylephrine; Postoperative Period; Pravastatin; Radial Artery; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Defensins are cysteine-rich cationic polypeptides released from neutrophils that exhibit powerful antimicrobial activities. Because inflammation, including neutrophil infiltration and release of defensins, may play an important role in atherosclerosis and other vascular diseases, we determined whether alpha-defensin could cause endothelial dysfunction, a major initial event of atherosclerosis, in porcine coronary arteries.. Porcine coronary arteries were sliced into 5-mm rings and treated with different concentrations of human recombinant alpha-defensin for 24 hours. Vasomotor reactivity was studied by using a myograph system. Levels of superoxide anion were detected by the lucigenin-enhanced chemiluminescence method. Endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein levels were determined by real-time polymerase chain reaction and immunohistochemistry analysis, respectively.. Endothelium-dependent relaxation in response to bradykinin was significantly reduced by 40% for the rings treated with 1500 nM of alpha-defensin compared with controls (P< .05). Vessel contractility in response to the thromboxane A2 analogue U46619 and endothelium-independent relaxation in response to sodium nitroprusside were not affected with defensin treatment. In addition, the superoxide anion level at the endothelial layer of porcine coronary artery rings was significantly increased by 80% in the defensin-treated (1500 nM) vessels compared with controls (P< .05). Furthermore, the eNOS mRNA levels in endothelial cells isolated from the cultured rings treated with defensin (1500 nM) were significantly decreased by 27% compared with controls (P< .05). Immunoreactivity of eNOS in the defensin-treated vessel rings was also substantially reduced.. Defensin reduces the endothelium-dependent vasorelaxation. This effect is associated with increased superoxide radical production and decreased eNOS expression in porcine coronary arteries.. Inflammation is an important mechanism of atherosclerosis and other vascular diseases. The roles and interactions of biomediators released from inflammatory cells are not fully understood, however. This study provides new information about effects and potential molecular mechanisms of a major neutrophil releasing factor, alpha-defensin, on endothelial dysfunction of porcine coronary arteries. Thus, targeting alpha-defensin and its associated molecular mechanisms may become a new strategy to prevent vascular diseases.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; alpha-Defensins; Animals; Bradykinin; Coronary Artery Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Humans; Nitric Oxide Synthase Type III; Nitroprusside; Recombinant Proteins; RNA, Messenger; Superoxides; Sus scrofa; Tissue Culture Techniques; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Homocysteine (Hcy) is an independent risk factor for atherosclerosis. This study investigates the effects of ginsenoside Rb1, a major constituent of ginseng, on Hcy-induced endothelial dysfunction and molecular changes in porcine coronary arteries.. The coronary arteries were harvested from pig hearts and cut into 5-mm ring segments, which were then divided into six groups, including control, Hcy alone (50 microM), low-dose (1 microM) or high-dose (10 microM) Rb1 alone, and Hcy plus low-dose or high-dose Rb1. After 24-hour incubation, the rings were analyzed for vasomotor function in response to thromboxane A2 analog U46619, bradykinin, and sodium nitroprusside (SNP), respectively. In addition, superoxide anion was assessed by lucigenin-enhanced chemiluminescence analysis. Endothelial nitric oxide synthase (eNOS) was studied using real-time polymerase chain reaction and Western blot.. Endothelium-dependent relaxation (bradykinin) was significantly reduced in rings treated with Hcy alone as compared with the control (49.80% vs 71.77%, n = 8, P < .05), whereas neither high-dose nor low-dose Rb1 alone affected the endothelium-dependent relaxation. The low-dose Rb1-Hcy combined group had a partially improved endothelium-dependent relaxation (54.44%), whereas the high-dose Rb1-Hcy combined group showed a complete recovery of endothelium-dependent relaxation (72.89%). There was no substantial difference in maximal contraction induced by U46619 or endothelium-independent relaxation by SNP among all groups (P > .05). Furthermore, superoxide anion was markedly increased by 137% in the Hcy-treated group as compared with the control, but there were no statistically significant changes from the control in all other groups (P > .05). Lastly, eNOS mRNA and protein levels were substantially reduced in the Hcy-treated group, but not in the Rb1-Hcy combined groups.. This is the first study to show that ginsenoside Rb1 can effectively block Hcy-induced endothelial dysfunction and superoxide anion production as well as eNOS downregulation in porcine coronary arteries. This study suggests that ginseng and its active constituents may have potential clinical applications in controlling Hcy-associated vascular injuries.. Homocysteine (Hcy) is an independent risk factor for atherosclerosis and other vascular lesions. It causes endothelial dysfunction and oxidative stress. Ginseng compounds have effects of vasorelaxation and antioxidation. The purpose of this study was to determine the effect of ginsenoside Rb1, a major constituent of ginseng, on Hcy-induced endothelial dysfunction and molecular changes in porcine coronary arteries. Our results showed that ginsenoside Rb1 can effectively block Hcy-induced dysfunction of endothelium-dependent vasorelaxation as well as superoxide anion production and eNOS downregulation. This study suggests that ginseng compounds may have potential clinical applications in controlling Hcy-associated vascular diseases and other vascular lesions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blotting, Western; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Down-Regulation; Endothelium, Vascular; Ginsenosides; Homocysteine; Immunohistochemistry; In Vitro Techniques; Luminescent Measurements; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; RNA, Messenger; Superoxides; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Constriction in response to serotonin is enhanced in the coronary arteries of atherosclerotic monkeys. The main objective of the present study was to determine whether abnormal responses to serotonin in atherosclerosis are reversed following removal of dietary cholesterol. In addition, we examined the effect of an atherogenic diet and reduction in dietary cholesterol on vascular responses to activation of ATP-sensitive K+ channels with aprikalim. Diameters of small coronary arteries were measured on the epicardial surface of the left ventricle in vivo by using stroboscopic illumination synchronized to the heart cycle to visually freeze the motion of the heart. Diameters were measured with a microscope-video system during topical application of two vasoconstrictor agonists, serotonin and the thromboxane mimetic U46619, and the vasodilator agonists aprikalim and nitroprusside. Responses were compared in normal (n = 9), atherosclerotic (n = 14; high-cholesterol diet), and regression (n = 8; high-cholesterol diet followed by normal diet) monkeys. Constriction of coronary arteries in response to serotonin was enhanced in monkeys on an atherogenic diet and was normal in regression monkeys. Vasoconstriction in response to U46619 and vasodilation in response to nitroprusside and aprikalim were not altered by atherosclerosis. Thus, abnormal vascular responses to serotonin in small coronary arteries of atherosclerotic monkeys without morphological evidence of disease can be reversed to normal by reducing dietary cholesterol.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Cholesterol, Dietary; Coronary Artery Disease; Coronary Vessels; Macaca fascicularis; Male; Nitroprusside; Picolines; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pyrans; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

In rat hepatocyte cultures daltroban reduced 14C-acetate incorporation stronger into cholesterol (CH) esters than into free CH. Further data suggest that the reduction of cellular sterols by daltroban is independent from its TXA2 receptor antagonistic activity and caused by reduced capacity of ACAT depending CH esterification. In rabbits fed CH-enriched diet treatment with daltroban led to an inhibition of platelet aggregation and to a significant reduction of progression of atherosclerosis. Both reduced CH esterification and TXA2 receptor antagonism may contribute to the diminution of progression of atherosclerosis by daltroban.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cells, Cultured; Cholesterol Esters; Coronary Artery Disease; Diet, Atherogenic; In Vitro Techniques; Lipid Metabolism; Male; Microsomes; Phenylacetates; Prostaglandin Endoperoxides, Synthetic; Rabbits; Rats; Sterol O-Acyltransferase; Sulfonamides; Thromboxanes; Vasoconstrictor Agents